Safety and Efficacy of Selinexor in Combination With Pembrolizumab in Recurrent Advanced Melanoma

NCT04768881 | Terminated Phase 2 Results DMC FDA Drug

• 1 other identifier: XPORT-MEL-033
• Study Type: interventional
• Target: 15
• Locations: 1 country
• Sites: 13

Brief Summary

Approximately 40 participants with locally advanced or metastatic melanoma will be enrolled in 20 sites in the United States into 1 of the following 2 arms: Primary resistance to initial checkpoint inhibitor (CPI) therapy in Arm A and Acquired resistance to initial CPI therapy in Arm B. Participants who have disease progression (PD) after discontinuation of CPIs, especially in neoadjuvant or adjuvant therapy, will be considered to have acquired resistance in this study. Participants will receive study treatment (Selinexor and Pembrolizumab) until PD, intolerable toxicity or withdrawal from the study, whichever occurs first.

Conditions

Locally Advanced Unresectable or Metastatic Melanoma

Keywords

Karyopharm; Locally advanced unresectable or metastatic melanoma; KPT-330; Recurrent advanced melanoma; Selinexor; Pembrolizumab

Outcome Measures

Primary Outcomes (1)

• Overall Response Rate (ORR) Assessed as Per Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1

  ORR was defined as the percentage of participants who achieved complete response (CR) or partial response (PR). ORR was assessed by RECIST 1.1 as defined by the Investigator based on radiologic criteria. Per RECIST 1.1 criteria, CR was defined as disappearance of all target lesions, any pathological lymph nodes (whether target or non-target) with reduction in short axis to less than (\<)10 millimeter (mm). PR was defined as at least a 30 percentage (%) decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

  From the date of randomization until the documentation of CR or PR, whichever occurs first (up to 24 months)

Secondary Outcomes (10)

• Progression-free Survival (PFS) as Per RECIST v 1.1

  From the date of randomization until disease progression or death, due to any cause (up to 24 months)

• Overall Survival (OS)

  From the date of first study treatment up to death (up to 24 months)

• Complete Response Rate (CRR)

  Up to 101 weeks

• Duration of Response (DOR) as Per RECIST v 1.1

  From first occurrence of CR or PR until disease progression or death, whichever occurs first (up to 24 months)

• Percentage of Participants With Disease Control Rate (DCR) as Per RECIST v 1.1

  Up to 24 months

Study Arms (2)

Arm A: Primary resistance to Initial CPI Therapy

EXPERIMENTAL

Participants will receive a dose of 80 milligrams (mg) selinexor orally once weekly (QW) and a dose of pembrolizumab 400 mg intravenously (IV) once in every six weeks (Q6W), both on Day 1 of a 6-week cycle until progressive disease (PD), intolerable toxicity or withdrawal from the study, whichever occurs first.

Drug: Selinexor; Drug: Pembrolizumab

Arm B: Acquired Resistance to Initial CPI Therapy

EXPERIMENTAL

Participants will receive a dose of 80 mg selinexor orally once weekly (QW) and a dose of pembrolizumab 400 mg IV Q6W, both on Day 1 of a 6-week cycle until PD, intolerable toxicity or withdrawal from the study, whichever occurs first.

Drug: Selinexor; Drug: Pembrolizumab

Interventions

Selinexor DRUG

Dose and formulation: 80 mg (4 tablets of 20 mg)

Also known as: KPT-330, XPOVIO®

Arm A: Primary resistance to Initial CPI Therapy; Arm B: Acquired Resistance to Initial CPI Therapy

Pembrolizumab DRUG

Dose and formulation: 400 mg (25 milligrams per milliliter \[mg/mL\]) Solution

Also known as: KEYTRUDA®

Arm A: Primary resistance to Initial CPI Therapy; Arm B: Acquired Resistance to Initial CPI Therapy

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age greater than or equal to (≥) 18 years at the time of informed consent.
• Participant must have a histologically confirmed diagnosis of locally advanced unresectable stage III or metastatic stage IV melanoma not amenable to local therapy.
• Participants must have confirmed PD per Response Evaluation Criteria in Solid Tumors (RECIST) on or within 12 weeks of the last dose of anti-PD-1/L1 monotherapy or combination therapy (including relatlimab or other anti-LAG-3 mAb) per Society for Immunotherapy in Cancer Guidelines (Kluger,2020).
• Arm A (primary resistance): participant has disease progression after receiving at least 6 weeks of prior anti-PD-1/L1 mAb with the best response as PD, or stable disease (SD) less than (\<) 6 month (participants with a partial response \[PR\] or complete response \[CR\] who have disease progression within 6 months will be considered to have primary resistance in this study).
• Arm B (secondary/acquired resistance): participant has disease progression after receiving at least 6 months of prior anti-PD-1/L1 mAb with the best response as CR, PR, or SD greater than (\>) 6 months (participants who have disease progression after neoadjuvant or adjuvant therapy, will be considered to have secondary resistance in this study).
• Participants who progress on or within 12 weeks after elective discontinuation of anti-PD-1/L1 mono or combination treatment in the absence of PD or treatment limiting toxicity must have confirmed PD per RECIST.
• Participants should have at least 1 prior line of CPI therapy but no more than 2.
• Measurable disease according to RECIST v1.1.
• Participants with stable previously treated brain metastases are permitted in this study.
• Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to (≤) 1.
• Adequate bone marrow function at screening, defined as:
• Absolute neutrophil count (ANC) ≥1.5 \* 10\^9 per liter (L).
• Hemoglobin ≥10 gram per deciliter (gm/dL) (≥6.2 millimoles per liter \[mmol/L\]).
• Platelet count ≥100 \* 10\^9/L.
• Serum direct bilirubin ≤1.5 \* upper limit of normal (ULN); aspartate transaminase (AST) and alanine transaminase (ALT) ≤2.5 \* ULN (with confirmed liver metastases: AST and ALT ≤5 \* ULN).

You may not qualify if:

• Metastatic uveal or ocular melanoma.
• Active central nervous system (CNS) metastases or other CNS (e.g., meningeal) involvement.
• Participants must have resolution or improvement of immune-mediated treatment related adverse reactions related to prior treatment(s) to Grade ≤1 without steroid maintenance therapy or his or her previous baseline prior to the corresponding CPI therapy
• a. History of immune-mediated treatment related adverse reactions leading to discontinuation of prior anti-programmed death protein 1 (PD-1), anti-programmed death protein ligand 1 (PD-L1), or anti programmed death protein ligand 2 (PD-L2) monoclonal antibodies (mAbs) or severe hypersensitivity reaction to any mAb or any excipients which in the opinion of the Investigator precludes future use of anti-PD-1/PDL1 therapy.
• Concurrent systemic steroid therapy higher than physiologic dose (\>10 milligrams per day \[mg/day\] of prednisone or equivalent).
• Previous treatment with selinexor or other exportin 1 (XPO1) inhibitors.
• Insufficient time since or not recovered from procedures or anti-cancer therapy, defined as:
• Not recovered from major surgery ≤28 days prior to Day 1 dosing. Minor procedures, such as biopsies, dental work, or placement of a port or intravenous (IV) line for infusion are permitted.
• Have ongoing clinically significant anti-cancer therapy-related toxicities Common Terminology Criteria for Adverse Events (CTCAE) Grade \>1. In specific cases, participants whose toxicity has stabilized or with Grade 2 non-hematologic toxicities can be allowed following documented approval by the Sponsor's Medical Monitor
• Had last dose of previous anti-cancer therapy ≤14 days prior to Day 1 dosing
• Palliative radiotherapy \>14 days prior to the study is allowed
• Received investigational drugs in other clinical trials within 28 days, or 5 half-lives of the investigational drug (whichever is shorter), prior to Cycle 1 Day 1 (C1D1).
• Live-attenuated vaccine (e.g., nasal spray influenza vaccine) ≤14 days prior to the intended C1D1.
• Impairment of gastrointestinal (GI) function or GI disease that could significantly alter the absorption of selinexor (e.g., vomiting, or diarrhea that is CTCAE version 5.0 grade \>1).
• Life expectancy less than (\<) 4 months based on the opinion of the Investigator

Sponsors & Collaborators

• Karyopharm Therapeutics Inc: lead

Study Sites (13)

UCLA

Los Angeles, California, 90095, United States

Location

TOI Clinical Research

Pasadena, California, 91105, United States

Location

BRCR Global

Plantation, Florida, 33322, United States

Location

Minnesota Oncology Hematology

Minneapolis, Minnesota, 55404, United States

Location

Great Plains Health

North Platte, Nebraska, 69101, United States

Location

John Theurer Cancer Center at Hackensack University Medical Center

Hackensack, New Jersey, 07601, United States

Location

Rutgers Cancer Institute of New Jersey

New Brunswick, New Jersey, 08901, United States

Location

New York Oncology Hematology

Albany, New York, 12206, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

Location

OH Care Clinical Trials

Cincinnati, Ohio, 45242, United States

Location

Cleveland Clinic Foundation

Cleveland, Ohio, 44144, United States

Location

Texas Oncology-Austin Central

Austin, Texas, 78731, United States

Location

Texas Oncology - Baylor Sammons Center

Dallas, Texas, 75246, United States

Location

MeSH Terms

Conditions

Melanoma

Interventions

selinexor; pembrolizumab

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases

Limitations and Caveats

This study was stopped prematurely due to a lack of sufficient anti-tumor signal for the selinexor/pembrolizumab combination treatment in participants with advanced or metastatic melanoma.

Results Point of Contact

• Title: Karyopharm Medical Information
• Organization: Karyopharm Therapeutics Inc

clinicaltrials@karyopharm.com

(888) 209-9326

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 22, 2021
• First Posted: February 24, 2021
• Study Start: May 12, 2021
• Primary Completion: September 22, 2023
• Study Completion: September 22, 2023
• Last Updated: August 23, 2024
• Results First Posted: August 23, 2024

Record last verified: 2024-08

Locations

US (13)